Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0025362 (mental retardation)
 15,878 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Renal angiomyolipoma is common in the tuberous sclerosis complex (TSC), the classic features of which are facial angiofibroma, seizures, and mental retardation. We report a family with three affected members demonstrating the wide spectrum of TSC-associated lesions ranging from asymptomatic findings to life-threatening complications. The predominant symptoms of the index patient were hypertension and mild renal insufficiency at age 48, resulting in end-stage renal failure at age 63 due to giant bilateral angiomyolipoma of the kidneys. The two TSC-affected siblings had died years previously, one from pulmonary lymphangioleiomyomatosis and the other during an epileptic state; the latter had situs inversus totalis as another remarkable finding. The diagnosis of TSC may be overlooked if CNS symptoms are absent and if cutaneous lesions are masked by cosmetic procedures, as occurred in the index case. Chronic renal failure due to angiomyolipoma is not widely known to clinical nephrologists, but develops in approximately 15% of TSC patients. Displacement of functional renal parenchyma by abnormal tissue appears to be the major pathogenetic mechanism leading to end-stage renal failure. Angiomyolipomas can be diagnosed from this characteristic sonographic pattern and the demonstration of fatty tissue in CT or MRI. Multiple renal cysts are also common in TSC. Therefore TSC should be considered in the differential diagnosis of polycystic kidney disease.
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PMID:Tuberous sclerosis complex with end-stage renal failure. 779 29

The tuberous sclerosis complex (TSC) is a multisystem autosomal dominant disorder characterized by seizures, mental retardation, and hamartomas. Patients with TSC have been reported to develop renal cell carcinomas (RCC) with increased frequency, an observation that is supported by the Eker rat model. To address the role of the tuberous sclerosis tumor suppressor genes in the pathogenesis of RCC, we studied six TSC-associated RCCs. Our findings suggest that some TSC-associated RCCs have clinical, pathological, or genetic features distinguishing them from sporadic RCC. Clinically, the TSC-associated tumors occurred at a younger age (mean, 36 years) than sporadic tumors and occurred primarily in women. Four of the six patients died of metastatic disease. Pathologically, five tumors displayed clear cell morphology. Of those five, two had high-grade spindle cell areas and one had granular cell histology in addition to the clear cell areas. A sixth tumor was anaplastic throughout. Four of the six tumors immunostained positively for a melanocyte-associated marker, HMB-45. HMB-45 positivity has been seen in two other TSC lesions: renal angiomyolipomas and pulmonary lymphangiomyomatosis. Five tumors were analyzed for loss of heterozygosity. Two had loss of heterozygosity on chromosome 9q34 and one had loss of heterozygosity on chromosome 16p13. We conclude that TSC-associated RCCs occur at an earlier age than sporadic RCCs, that some TSC-associated renal carcinomas have a different immunophenotype than sporadic RCCs, and that the TSC tumor suppressor genes may play a specific pathogenic role in these tumors.
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PMID:Tuberous sclerosis-associated renal cell carcinoma. Clinical, pathological, and genetic features. 886 69

Lymphangiomyomatosis (LAM) is a rare disease, of unknown etiology, affecting women almost exclusively. Lung transplantation is the only consistently effective therapy for LAM. Microscopically, LAM consists of a diffuse proliferation of smooth muscle cells. LAM can occur without evidence of other disease (referred to as "sporadic LAM") or in association with tuberous sclerosis complex (TSC). TSC is an autosomal dominant tumor suppressor gene syndrome characterized by seizures, mental retardation, and tumors in the brain, heart, skin, and kidney. Renal angiomyolipomas occur in approximately 50% of sporadic LAM patients and in 70% of TSC patients. Loss of heterozygosity (LOH) in the chromosomal region for the TSC2 gene occurs in 60% of TSC-associated angiomyolipomas. Because of the similar pulmonary and renal manifestations of TSC and sporadic LAM, we hypothesized that LAM and TSC have a common genetic basis. We analyzed renal angiomyolipomas, from 13 women with sporadic LAM, for LOH in the regions of the TSC1 (chromosome 9q34) and TSC2 (chromosome 16p13) genes. TSC2 LOH was detected in seven (54%) of the angiomyolipomas. We also found TSC2 LOH in four lymph nodes from a woman with retroperitoneal LAM. No TSC1 LOH was found. Our findings indicate that the TSC2 gene may be involved in the pathogenesis of sporadic LAM. However, genetic transmission of LAM has not been reported. Women with LAM may have low-penetrance germ-line TSC2 mutations, or they may be mosaic, with TSC2 mutations in the lung and the kidney but not in other organs.
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PMID:Evidence that lymphangiomyomatosis is caused by TSC2 mutations: chromosome 16p13 loss of heterozygosity in angiomyolipomas and lymph nodes from women with lymphangiomyomatosis. 952 62

Tuberous sclerosis complex (TSC) is an autosomal-dominant disorder characterized by mental retardation, seizures, and central nervous system and visceral hamartomas. Pulmonary involvement manifesting as lymphangioleiomyomatosis (LAM) occurs in 1% of patients (all women) with TSC. Micronodular pneumocyte hyperplasia also has been described as a rare pulmonary manifestation of TSC. We report 14 patients with micronodular pneumocyte hyperplasia (MNPH). The patients ranged in age from 23 to 57 years (mean 37.5). There were 12 women and 2 men. Nine of the patients (one man and eight women) had documented clinical manifestations of TSC: seven with LAM, two without LAM (including one man). Of the five patients who did not have TSC, three had LAM and two did not (including one man). Histologically, all 14 cases demonstrated multiple well-demarcated nodules usually measuring up to 8 mm in size, but most were 1-3 mm. The nodules were produced by a proliferation of enlarged cytologically benign type II pneumocytes, with an associated increase in alveolar macrophages and interstitial reticulin. Immunoperoxidase studies showed the type II pneumocytes within lesions to be reactive with antibodies to cytokeratin (four of four), epithelial membrane antigen (EMA) (five of five), and surfactant apoprotein B (8 of 10). HMB-45 was negative in the MNPH lesions in all nine cases studied. Follow-up was available in 9 of 10 living patients and ranged from 1 to 14 years (mean 6 years). Nine patients are alive; six are clinically stable and three have repeated pneumothoraces related to LAM. Four patients have died. None of the deaths were attributable to MNPH. MNPH appears to be a hamartomatous proliferation occurring most frequently in patients with tuberous sclerosis, is separable from and not a manifestation of LAM, has been observed to occur in men, and, like other hamartomas of tuberous sclerosis, does not appear to possess malignant potential.
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PMID:Micronodular pneumocyte hyperplasia. 953 75

Pulmonary lymphangioleiomyomatosis (LAM) is a rare disorder limited almost exclusively to women of reproductive age. LAM affects about 5% of women with tuberous sclerosis complex (TSC). LAM also occurs in women who do not have TSC (sporadic LAM). TSC is a tumour suppressor gene syndrome characterised by seizures, mental retardation, and tumours in the brain, heart, and kidney. Angiomyolipomas, which are benign tumours with smooth muscle, fat, and dysplastic vascular components, are the most common renal tumour in TSC. Renal angiomyolipomas also occur in 63% of sporadic LAM patients. We recently found that 54% of these angiomyolipomas have TSC2 loss of heterozygosity, leading to the hypothesis that sporadic LAM is genetically related to TSC. In this study, we screened DNA from 21 women with sporadic LAM for mutations in all 41 exons of TSC2. Twelve of the patients had known renal angiomyolipomas. No TSC2 mutations were detected. We did find three silent TSC2 polymorphisms. We conclude that patients with sporadic LAM, including those with renal angiomyolipomas, do not have a high frequency of germline mutations in the coding region of TSC2.
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PMID:Mutational analysis of the tuberous sclerosis gene TSC2 in patients with pulmonary lymphangioleiomyomatosis. 1063 37

Secondary pneumothorax occurs as a symptom of an underlying pulmonary disease. We report the case of an 18-year-old woman with tuberous sclerosis (Bourneville's disease) and recurrent pneumothoraces. Clinical outcome was favorable 6 months after bilateral videothoracoscopic pleurectomy. The complete triad of tuberous sclerosis (TS) (mental retardation, seizures, adenoma sebacium) is not always present in those who develop pulmonary involvement. When TS involves the lung it is clinically and pathologically indistinguishable from lymphangioleiomyomatosis (LAM). The very rare pulmonary involvement of TS and LAM are problems primarily of women in childbearing age. A pneumothorax can be the first symptom of TS or LAM.
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PMID:[Secondary spontaneous pneumothorax in tuberous sclerosis]. 1182 39

Tuberous sclerosis complex (TSC) is a tumor suppressor gene syndrome characterized by seizures, mental retardation, autism, and tumors of the brain, kidney, heart, retina, and skin. TSC is caused by mutations in either TSC1 or TSC2, both of which are tumor suppressor genes. Hamartin, the protein product of TSC1, was found to interact with the ezrin-radixin-moesin family of cytoskeletal proteins and to activate the small GTPase Rho. To determine whether tuberin, the TSC2 product, can also activate Rho, we stably expressed full-length human tuberin in two cell types: MDCK cells and ELT3 cells. ELT3 cells lack endogenous tuberin expression. We found that expression of human tuberin in both MDCK and ELT3 cells was associated with an increase in the amount of Rho-GTP, but not in Rac1-GTP or cdc42-GTP. Tuberin expression increased cell adhesion in both cell types, and decreased chemotactic cell migration in ELT3 cells. In MDCK cells, there was a decrease in the amount of total Focal Adhesion Kinase (FAK) and an increase in the fraction of phosphorylated FAK. These findings demonstrate for the first time that tuberin activates Rho and regulates cell adhesion and migration. Pathways involving Rho activation may have relevance to the clinical manifestations of TSC, including pulmonary lymphangioleiomyomatosis.
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PMID:Tuberin, the tuberous sclerosis complex 2 tumor suppressor gene product, regulates Rho activation, cell adhesion and migration. 1246 66

This review is focused on pathways and mechanisms that might provide molecular links between the pathogenesis of renal and pulmonary disease in tuberous sclerosis complex and the pathogenesis of the neurologic manifestations of tuberous sclerosis complex. Tuberous sclerosis complex is an autosomal dominant disorder in which the manifestations can include seizures; mental retardation; autism; benign tumors of the brain, retina, skin, and kidneys; and pulmonary lymphangiomyomatosis. Lymphangiomyomatosis is a life-threatening lung disease affecting almost exclusively young women. Genetic data have demonstrated that the cells giving rise to renal angiomyolipomas, the most frequent tumor type in patients with tuberous sclerosis complex, exhibit differentiation plasticity. Genetic studies have also shown that the benign smooth muscle cells of angiomyolipomas and pulmonary lymphangiomyomatosis have the ability to migrate or metastasize to other organs. These findings indicate that hamartin and tuberin play functional roles in the regulation of cell migration and differentiation. The biochemical pathways responsible for these effects are not yet fully understood but might involve dysregulation of the small guanosine triphosphatase Rho. Similar pathways might contribute to aberrant neuronal differentiation and migration in tuberous sclerosis complex.
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PMID:Aberrant cellular differentiation and migration in renal and pulmonary tuberous sclerosis complex. 1556 18

Tuberous sclerosis complex (TSC) is a tumor suppressor gene syndrome whose manifestations can include seizures, mental retardation, autism, and tumors in the brain, retina, kidney, heart, and skin. The products of the TSC1 and TSC2 genes, hamartin and tuberin, respectively, heterodimerize and inhibit the mammalian target of rapamycin (mTOR). This review focuses on the genetic and biochemical basis of the renal and pulmonary manifestations of TSC, angiomyolipomas, and lymphangiomyomatosis, respectively. Genetic analyses of sporadic angiomyolipomas revealed that all three components (smooth muscle, vessels, and fat) derive from a common progenitor cell, indicating the ability of cells lacking tuberin to differentiate into multiple lineages. Other genetic studies showed that the benign smooth muscle cells of pulmonary lymphangiomyomatosis have the ability to migrate to other organs. These findings suggest that tuberin and hamartin play a role in the regulation of cellular migration and differentiation. We have found that tuberin activates B-Raf kinase and p42/44 MAPK and that cells lacking tuberin have low levels of B-Raf activity. We hypothesize that aberrant B-Raf activity in angiomyolipomas leads to abnormal cellular differentiation and migration.
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PMID:The role of tuberin in cellular differentiation: are B-Raf and MAPK involved? 1638 52

Tuberous sclerosis (TSC) is an autosomal dominant disorder with the incidence of 1/10 000. The disease is characterized by epilepsy, mental retardation, the occurrence of hamartomas in the various organs and angiomyolipomas in the kidney. According to the literature lung changes identical with lymphangioleiomyomatosis (LAM) occur in over 30% of TSC patients. We report on 6 cases diagnosed in our department in last 14 years. This is the largest group of patients with TSC and LAM collected in one center in Poland. All patient were women. The diagnosis of LAM was confirmed by lung biopsy in 5 patients and established on the basis of clinical presentation, lung function tests and high resolution computerized tomographic scanning (HRCT) of the lung in 1 case. The mean age at diagnosis of TSC was 21 years and at the diagnosis of LAM was 28 years. Typical skin changes, angiomyolipomas of the kidney and calcifications in the brain were documented in all patients, 4 patients had nefrectomy and 4 had at least one episode of sponateous pneumothorax. Epilepsy was diagnosed in 4 of 6 cases and mental retardation in 1 (17%). Abnormal values in pulmonary function tests were common. All but one demonstrated decrease in diffusing capacity (DLCO) below 80% of predicted. 5 out of 6 had FEV1 below 80% of predicted but only 3 had FEV1%VC below 80%. Only 3 patients were given antiestrogen therapy which was medroxyprogesterone in 2 cases and tamoxifen in 1. We are unable to conclude on the efficacy of treatment due to small number of treated patients. We conclude that TSC should be suspected in LAM patients and LAM should be considered in all women with the diagnosis of TSC.
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PMID:[Pulmonary disease in patients with tuberous sclerosis]. 1653 84


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